The present invention relates to a non-invasive apparatus system for non-invasively monitoring autonomic nervous system and the use thereof in monitoring autonomic nervous system functional change side effects, which are caused by drugs or aging of autonomic nervous system, and the methods for tracing therapeutic effect by using the same.
In view of the world population having the tendency of aging and the increasing population suffering from chronic diseases caused by aging, the pharmaceutical companies around the world have been developing new drugs for treating the chronic diseases to improve life qualities. However, in addition to the desired activities, many drugs being or to be marketed are usually accompanied with several side effects, including the influences to autonomic nerves (sympathetic and parasympathetic nerves). Autonomic nerves control several important conscious and unconscious activities in human, such as heart rate, blood pressure, blood sugar, sleeping, sweating, bowel peristalsis, and bronchodilation. Therefore, if a drug has any harmful inference, it may cause severe diseases (e.g. hypertension or arrhythmia) or abnormality (e.g. insomnia or unregulated body temperature), and the physical and mental health of the patients will be affected. This type of cases has been commonly described in clinical articles and market reports. For example, as reported in American Associated Press (25 Aug. 2001), GlaxoSmithKline PLC, a pharmaceutical company in the United Kingdom, was accused by a group of American patients for the reason that its drug Paxil, for treating depression may cause side effects to sympathetic and central nervous system, which include causing seizure, night sweating, and suicidal thought. Although pharmaceutical companies and doctors have been aware of the side effects on autonomic nerves, there is currently no effective means to resolve the problems of side effects caused by drugs. Furthermore, no methods and techniques for directly monitoring these side effects are available.
Nowadays, in the duration of developing new drugs, all pharmaceutical companies in the world measure the nervous toxicity of the new drugs by animal models. Normally, only the drugs having low toxicity can enter the clinical trial stage. During the human clinical trials, doctors can merely investigate orally or by questionnaire to determine whether the drug influences the normal functions of the autonomic nervous system, such as the appearance of the syndromes of insomnia, blushing, palpitation, and dizziness, and by associating with measurement of blood pressure and heart rate to determine the patient""s responses of autonomic nervous system. However, in many cases, acute or chronic side effects of drugs are caused or amplified by drug-drug interactions resulting from several drugs being taken by the patients simultaneously. It is impossible to test all combinations of drugs during the clinical trials, so that the problems caused by side effects happen again and again.
Additionally, according to the experiences of the clinical trials, the acute and severe side effects only happen to a very low percentage (usually smaller than 0.1%) of patients taking medicines. Therefore, according to the statistics, an acute and severe side effect to autonomic nervous system will not be found in a clinical trial of less than one thousand patients. Even in a clinical trail of ten thousand patients (few pharmaceutical companies would hold a clinical trial in such a large scale), only about ten severe cases would happen. In light of the special case having a probability of less than 1%, it is classified as an xe2x80x9cunknown reasonxe2x80x9d in general clinical trial reports and the data is removed from the normal analysis range. Consequently, the process of marketing the drug will continue without being hindered by the special cases. However, after a new drug is marketed, the cases of acute side effects increase suddenly (more than hundreds of people) because more than one million people are taking the drug. Under these circumstances, governmental health authorities, pharmaceutical companies and doctors may feel panicky about these cases and decide to withdraw the drug from the market. In 1997, American Home Product stopped selling a drug, Fen-Phen, intended for weight control, which has been approved for marketing by the U.S. Food and Drug Administration (FDA) in 1996 and had been taken by more than six million of people all over the world, for the reasons that the drug may severely damage heart valves and nervous system. The company was decided to pay a compensation of twenty seven million U.S. dollars to an American woman, and in a following class lawsuit, the estimated compensation is expected to be more than one billion U.S. dollars. Evidently, side effects and withdrawal of drugs will not only cause a loss of revenue profit but also a great deal of compensation in law suits.
In addition, oral or questionary investigations for tracing the influences of drugs in the outpatient department or clinic are not frequent enough to prevent acute side effects. Furthermore, patients (especially elder patients) usually incorrectly recognize or remember the syndromes caused by the autonomic nervous system (e.g. whether night sweating, accelerating heart rate, or dizziness really has happened or not). Therefore, the cases caused by side effects happen frequently.
In another aspect, various anti-aging drugs or treatment have been gradually developed with the aging population. Some doctors consider that aging process can be delayed and even the aged tissues can be rejuvenated by suitable treatments. Usually, the doctor would ask the patient to conduct a series of tests first to estimate the degree of aging. For example, if the amounts of growth hormone and sex hormone in the blood of a patient are lower than those of normal persons at the same age, this indicates that the patient""s xe2x80x9cphysiological agexe2x80x9d is older than his or her xe2x80x9cchronological or actual agexe2x80x9d. Doctors also use other physical methods to test the patient""s physiological functions. For example, the doctor allows the patient to lie down for a while and then asks the patient to stand suddenly to observe whether the patient will feel dizzy or can stand stably; or the doctor holds a small piece of paper (or dollar bill) and then releases it suddenly to observe whether the fingers of the patient awaiting below the paper can catch the paper fast enough. The phenomenon of dizziness is associate with a sudden change of blood pressure, which is regulated by autonomic nerve in human, and the test of catching a small piece of paper is associated with the brain function, nerve transmission and muscle contraction. However, these tests and other physical tests can only be used for qualitative evaluation, but not for quantitative determination. Doctors often prescribe drugs (e.g. hormones), physical treatments or nutrition supplements, or recommend increasing exercise to help their patients to delay aging and even to rejuvenate. However, these treating methods need a simple and quantitative assay method to trace the therapeutic effect. According to the published articles, no methods or apparatus systems have been found to be able to use heart rate variability or the similar information as the indicator of aging.
Therefore, a non-invasively and easily operative method and apparatus system for monitoring the functions of autonomic nervous system and for quantifying the aging physiological statuses are needed to avoid acute side effects and to help doctors in diagnosing the aging condition and tracing the treatment of aging.
Recently, Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology (Heart Rate Variability: Standards of Measurement, Physiological Interpretation and Clinical Use; Circulation 93:1043-1065; 1996) and Malliani et al. (Cardiovascular Neural Regulation Explored in the Frequency Domain; Circulation 84: 482-492; 1991) found that heart rate variability not only is affected by the undulation of respiratory, but also indicates the functions of the autonomic nervous system. The heart rate variability is related to the minute, cyclic change of heartbeat (i.e. heart rate). While heartbeat is normally maintained at 60-90 times per minute at rest, some regular or irregular oscillations have been found within the pulse data. These oscillations are very small, so that they cannot be accurately analyzed by the traditional analytical methods. Using the modern technologies of computer and spectral analysis, Akselrod et al (Power Spectrum Analysis of Heart Rate Fluctuation: A Quantitative Probe of Beat-to-Beat Cardiovascular Control; Science; 213:220-222; 1981 and Spectral Analysis of Fluctuations in Cardiovascular Parameters: A Quantitative Tool for the Investigation of Autonomic Control; Trends in Pharmacological Science; 9:6-9; 1988) and Kuo et al (Continuous, On-line, Real-time Spectral Analysis of Arterial Blood Pressure Using a Personal Computer; American Journal of Physiology; 264:H2208-H2213; 1993) discovered micro-oscillations in heart rate variability through the spectral analysis. They found that the micro-oscillations in heart rate variability can generally be divided into two groups: a high frequency (HF) variability and a low frequency (LF) variability. The low frequency variability can further be divided into a very low frequency variability and a low frequency variability. By way of animal and human tests, De Boer et al (Hemodynamic Fluctuations and Baroreflex Sensitivity in Humans: A Beat-to-Beat Model: American Journal of Physiology; 253:H680-H689; 1987) proved that the variance in heart rate variability, the total power (TP) and the high frequency (HF) are associated with the activity of parasympathetic nerves, and the ratio of low frequency variability to high frequency variability (LF/HF) and the percentage of low frequency variability (LF%) are associated with the activity of sympathetic nerves.
Many different methods can be used for measuring heart rate and variability thereof. Two methods are most commonly used. One is measuring patient""s artery pressure signal, which can be conducted invasively (by implanting a pressure sensor into the artery of human body) or non-invasively (by placing a pressure sensor on the skin surface near the artery); and the other is placing electrodes on patient""s chest to measure the electrocardiographic signal. The signals obtained from the methods can be converted into heart rate (HR). The heart rate is the reciprocal of the intervals between the peaks of the signals of the measured blood pressure or electrocardiograph. The micro oscillations of heart rate can be converted to spectrum by the Fourier Transform method and then further be divided into high frequency, low frequency and very low frequency variability according to their definitions. Based on the 2D Power Spectrum Density-Frequency graph, the power of each variability can be obtained by integrating the corresponding range of the frequency. Yang et al (Continuous, On-line, Real-Time Spectral Analysis of SAP Signals During Cardiopulmonary Bypass; American Journal of Physiology; 268:H2329-H2335; 1995) defined the human frequency ranges to be high frequency of 0.15-0.40 Hz, low frequency of 0.04-0.15 Hz and very low frequency of 0.003-0.04 Hz.
ROC (Taiwan) Patent Publication No. 363,404 discloses a heart rate variability analyzing electrocardiograph converter (with electrodes) for measuring the electric potential signal of heart contraction, wherein the heart rate variability is calculated from the signal by the Fourier Transform method and spectral analysis. However, the invention is to provide a novel heart rate variability analyzing electrocardiograph converter, which is characterized by the designation of new software and hardware, and the apparatus system containing the same.
The uses of monitoring the side effects to the autonomic nervous system caused by drugs, and measuring the xe2x80x9cphysiological agexe2x80x9d have neither been disclosed nor suggested in the prior art mentioned above.
The subject of the invention provides an apparatus system and a method which can discover and monitor the side effects to the autonomic nervous system caused by drugs at anytime, and can provide warning at the early stage to avoid severe side effects. The apparatus system and method of the present invention can also be used for tracing aging of autonomic nervous system by monitoring the activity of the autonomic nervous system.
The present invention provides a non-invasive apparatus system for monitoring the side effects to the autonomic nervous system caused by drugs to prevent acute or chronic side effects to the brain nerves; and for monitoring the aging of nervous system by measuring the xe2x80x9cphysiological agexe2x80x9d of the patient based on the activity of the autonomic nervous system.